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1.
CEN Case Rep ; 9(2): 177-181, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31989455

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder, characterized by the progressive formation of renal cysts. Although ADPKD is strongly associated with cerebral and cardiovascular complications, cerebral ischemia caused by dissection of thoracic and carotid arteries has rarely been reported. We report the case of a 71-year-old Japanese woman who complained of hemiparesis. She required maintenance hemodialysis therapy with a background of ADPKD. Cerebral infarction was initially diagnosed by excluding intracranial hemorrhage and aneurysm rupture that are recognized as common complications of ADPKD and thereby anticoagulation therapy was initiated. However, the patient was suspected as having painless aortic dissection because a chest X-ray examination showed expanded upper mediastinum. Sequential vascular imagings revealed dissection of the aorta, originating from brachiocephalic trunk to the right common carotid artery with mediastinal hematoma. The patient died from progression of dissection. Herein, we described a case of the ADPKD patient that an acute aortic dissection without any pain induced the occlusion of supplying vessels to the brain, resulting in cerebral ischemic symptoms. A high level of clinical vigilance for an acute aortic dissection should be maintained in the ADPKD population with sudden onset of neurological symptoms even in the absence of pain. Furthermore, the initiation of anticoagulation treatment for cerebral ischemia which may aggravate the risk of further dissection requires careful consideration.

2.
Endocr J ; 67(2): 153-160, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-31685720

RESUMO

Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD+) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD+ prevent these disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men. A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 h after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention. The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature. Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.

3.
Proc Natl Acad Sci U S A ; 116(47): 23822-23828, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31694884

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of ß-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD+-SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.


Assuntos
Adaptação Fisiológica , Tecido Adiposo Marrom/metabolismo , Metabolismo Energético , Homeostase , NAD/biossíntese , Termogênese , Tecido Adiposo Marrom/enzimologia , Animais , Caveolina 1/antagonistas & inibidores , Temperatura Baixa , Citocinas/genética , Jejum , Humanos , Camundongos , Camundongos Knockout , Mononucleotídeo de Nicotinamida/administração & dosagem , Nicotinamida Fosforribosiltransferase/genética
4.
Sci Rep ; 9(1): 913, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696889

RESUMO

The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2+SALL1+ nephron progenitor cells with 92% efficiency within 2 days. Subsequently, the second set - HNF1A, GATA3, GATA1 and EMX2, differentiated these cells into PAX8+LHX1+ pretubular aggregates in another 2 days. Further culture in both 2-dimensional and 3-dimensional conditions produced iNephLOs containing cells characterized as podocytes, proximal tubules, and distal tubules in an additional 10 days. Global gene expression profiles showed similarities between iNephLOs and the human adult kidney, suggesting possible uses of iNephLOs as in vitro models for kidneys.

5.
Mol Psychiatry ; 24(11): 1668-1684, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-29728703

RESUMO

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.


Assuntos
Ritmo Circadiano/fisiologia , Sirtuína 1/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Encéfalo/metabolismo , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Ritmo Circadiano/genética , Cocaína/metabolismo , Condicionamento Operante/fisiologia , Condicionamento Psicológico/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NAD/metabolismo , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Oxirredução , Recompensa , Sirtuína 1/fisiologia , Tirosina 3-Mono-Oxigenase/fisiologia , Área Tegmentar Ventral/metabolismo
6.
Am J Physiol Endocrinol Metab ; 315(4): E520-E530, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29634313

RESUMO

Mitochondrial dysfunction in adipose tissue is involved in the pathophysiology of obesity-induced systemic metabolic complications, such as type 2 diabetes, insulin resistance, and dyslipidemia. However, the mechanisms responsible for obesity-induced adipose tissue mitochondrial dysfunction are not clear. The aim of present study was to test the hypothesis that nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuin-3 (SIRT3) in adipocytes plays a critical role in adipose tissue mitochondrial biology and obesity. We first measured adipose tissue SIRT3 expression in obese and lean mice. Next, adipocyte-specific mitochondrial Sirt3 knockout (AMiSKO) mice were generated and metabolically characterized. We evaluated glucose and lipid metabolism in adult mice fed either a regular-chow diet or high-fat diet (HFD) and in aged mice. We also determined the effects of Sirt3 deletion on adipose tissue metabolism and mitochondrial biology. Supporting our hypothesis, obese mice had decreased SIRT3 gene and protein expression in adipose tissue. However, despite successful knockout of SIRT3, AMiSKO mice had normal glucose and lipid metabolism and did not change metabolic responses to HFD-feeding and aging. In addition, loss of SIRT3 had no major impact on putative SIRT3 targets, key metabolic pathways, and mitochondrial function in white and brown adipose tissue. Collectively, these findings suggest that adipocyte SIRT3 is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism. Contrary to our hypothesis, loss of SIRT3 function in adipocytes is unlikely to contribute to the pathophysiology of obesity-induced metabolic complications.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Metabolismo Energético/genética , Mitocôndrias/metabolismo , Sirtuína 3/genética , Animais , Dieta Hiperlipídica , Camundongos , Camundongos Knockout , Camundongos Obesos , Sirtuína 3/metabolismo
7.
J Clin Endocrinol Metab ; 103(3): 1068-1076, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29294006

RESUMO

Context: Many biological pathways involved in regulating substrate metabolism display rhythmic oscillation patterns. In rodents, clock genes regulate circadian rhythms of metabolic genes and substrate metabolism. However, the interrelationships among substrate metabolism, metabolic genes, and clock genes have not been fully explored in people. Objective: We tested the hypothesis that the diurnal expression pattern of pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic enzyme involved in fuel switching between glucose and free fatty acids (FFAs), is associated with plasma FFA concentration and clock genes. Design and Methods: We analyzed peripheral blood mononuclear cells (PBMCs), subcutaneous adipose tissue, and plasma samples obtained serially during 24 hours from metabolically healthy women (n = 10) and evaluated the interrelationships among PDK4, plasma FFA, and clock genes. We also determined the potential mechanisms responsible for PDK4 transcriptional regulation by using primary human PBMCs and adipocytes. Results: We found that PDK4 diurnal expression patterns were similar in PBMCs and adipose tissue (ρ = 0.84, P < 0.001). The diurnal variation in PBMC PDK4 expression correlated more strongly with plasma FFA and insulin (ρ = 0.86 and 0.63, respectively, both P < 0.001) concentrations than clock genes. Data obtained from primary culture experiments demonstrated that FFAs directly induced PDK4 gene expression, at least in part through activation of peroxisome proliferator-activated receptor α. Conclusions: Our results suggest that plasma FFA availability is an important regulator of diurnal expression patterns of PDK4, and we identify a novel interaction between plasma FFA and cellular diurnal rhythms in regulating substrate metabolism.


Assuntos
Ritmo Circadiano/fisiologia , Ácidos Graxos não Esterificados/sangue , Expressão Gênica/fisiologia , Proteínas Serina-Treonina Quinases/sangue , Adipócitos/fisiologia , Adulto , Proteínas CLOCK/sangue , Feminino , Voluntários Saudáveis , Humanos , Insulina/sangue , Leucócitos Mononucleares/fisiologia , Pessoa de Meia-Idade , PPAR alfa/fisiologia , Quinase Piruvato Desidrogenase (Transferência de Acetil) , Gordura Subcutânea/fisiologia , Transcrição Genética
8.
Bioessays ; 39(5)2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28295415

RESUMO

Nicotinamide adenine dinucleotide (NAD+ ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD+ biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD+ biosynthesis, together with its key downstream mediator, namely the NAD+ -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD+ biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD+ biology.


Assuntos
Tecido Adiposo/metabolismo , Resistência à Insulina/fisiologia , NAD/metabolismo , Obesidade/metabolismo , Animais , Humanos , Modelos Biológicos , Nicotinamida Fosforribosiltransferase/metabolismo , Obesidade/tratamento farmacológico , Obesidade/etiologia , PPAR gama/metabolismo , Processamento de Proteína Pós-Traducional , Sirtuína 1/metabolismo , Pesquisa Médica Translacional
9.
Sci Rep ; 6: 38353, 2016 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-27982115

RESUMO

Recent advances in stem cell research have resulted in methods to generate kidney organoids from human pluripotent stem cells (hPSCs), which contain cells of multiple lineages including nephron epithelial cells. Methods to purify specific types of cells from differentiated hPSCs, however, have not been established well. For bioengineering, cell transplantation, and disease modeling, it would be useful to establish those methods to obtain pure populations of specific types of kidney cells. Here, we report a simple two-step differentiation protocol to generate kidney tubular organoids from hPSCs with direct purification of KSP (kidney specific protein)-positive cells using anti-KSP antibody. We first differentiated hPSCs into mesoderm cells using a glycogen synthase kinase-3ß inhibitor for 3 days, then cultured cells in renal epithelial growth medium to induce KSP+ cells. We purified KSP+ cells using flow cytometry with anti-KSP antibody, which exhibited characteristics of all segments of kidney tubular cells and cultured KSP+ cells in 3D Matrigel, which formed tubular organoids in vitro. The formation of tubular organoids by KSP+ cells induced the acquisition of functional kidney tubules. KSP+ cells also allowed for the generation of chimeric kidney cultures in which human cells self-assembled into 3D tubular structures in combination with mouse embryonic kidney cells.


Assuntos
Técnicas de Cultura de Células/métodos , Túbulos Renais/citologia , Organoides/citologia , Células-Tronco Pluripotentes/citologia , Animais , Especificidade de Anticorpos/imunologia , Biomarcadores/metabolismo , Diferenciação Celular , Linhagem da Célula , Separação Celular , Reações Cruzadas/imunologia , Células HEK293 , Células-Tronco Embrionárias Humanas/citologia , Humanos , Camundongos Endogâmicos ICR
10.
Sci Rep ; 6: 36533, 2016 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-27827416

RESUMO

The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.


Assuntos
Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Túbulos Renais Proximais/metabolismo , Rim/lesões , Obesidade/complicações , Animais , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tamoxifeno/administração & dosagem
11.
Cell Rep ; 16(7): 1851-60, 2016 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-27498863

RESUMO

Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD(+) intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.


Assuntos
Adipócitos/enzimologia , Tecido Adiposo/enzimologia , Citocinas/genética , Resistência à Insulina/genética , Nicotinamida Fosforribosiltransferase/genética , Obesidade/genética , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Adiponectina , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Citocinas/deficiência , Ácidos Graxos não Esterificados/sangue , Feminino , Regulação da Expressão Gênica , Hipoglicemiantes/farmacologia , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Mononucleotídeo de Nicotinamida/farmacologia , Nicotinamida Fosforribosiltransferase/deficiência , Obesidade/enzimologia , Obesidade/patologia , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação , Rosiglitazona , Transdução de Sinais , Tiazolidinedionas/farmacologia
12.
J Am Soc Mass Spectrom ; 27(7): 1219-26, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27098411

RESUMO

We propose detecting a fragment ion (Ph2As(+)) using counter-flow introduction atmospheric pressure chemical ionization ion trap mass spectrometry for sensitive air monitoring of chemical warfare vomiting agents diphenylchloroarsine (DA) and diphenylcyanoarsine (DC). The liquid sample containing of DA, DC, and bis(diphenylarsine)oxide (BDPAO) was heated in a dry air line, and the generated vapor was mixed into the humidified air flowing through the sampling line of a mass spectrometer. Humidity effect on the air monitoring was investigated by varying the humidity of the analyzed air sample. Evidence of the in-line conversion of DA and DC to diphenylarsine hydroxide (DPAH) and then BDPAO was obtained by comparing the chronograms of various ions from the beginning of heating. Multiple-stage mass spectrometry revealed that the protonated molecule (MH(+)) of DA, DC, DPAH, and BDPAO could produce Ph2As(+) through their in-source fragmentation. Among the signals of the ions that were investigated, the Ph2As(+) signal was the most intense and increased to reach a plateau with the increased air humidity, whereas the MH(+) signal of DA decreased. It was suggested that DA and DC were converted in-line into BDPAO, which was a major source of Ph2As(+). Graphical Abstract ᅟ.

13.
Nihon Rinsho ; 74(9): 1447-1455, 2016 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-30557475

RESUMO

Nicotinamide adenine dinucleotide(NAD') is a classic coenzyme playing a critical role in cellular redox reactions. Emerging evidence demonstrates that NAD' and its key mediators, NAD+-dependent protein deacetylases (sirtuins), together regulate many important meta- bolic pathways including mitochondrial function. Thus, impaired NAD' biosynthesis is critically involved in the pathophysiology of aging and age-associated diseases. Importantly, administration of key NAD+ intermediates, such as nicotinamide mononucleotide(NMN) or nicotinamide riboside (NR), improves mitochondrial function and exerts remarkable therapeutic effects for various age-associated diseases, such as diabetes and cancer, in mice. In this review, we will summarize and discuss pathophysiological relevance and translational potential of NAD' biology and mitochondrial sirtuin(SIRT3) in age-associated diseases.


Assuntos
Envelhecimento , Mitocôndrias , Processamento de Proteína Pós-Traducional , Sirtuína 3 , Envelhecimento/fisiologia , Animais , Humanos , Hidrolases , Camundongos , Mitocôndrias/metabolismo , Niacinamida/análogos & derivados , Proteômica , Sirtuína 3/fisiologia
14.
Clin Exp Nephrol ; 20(3): 394-401, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26373846

RESUMO

BACKGROUND: microRNAs (miRNAs) are non-coding small RNAs that regulate embryonic development, cell differentiation and pathological processes via interaction with mRNA. Epithelial-mesenchymal transition (EMT) is pathological process that involves in a variety of diseases such as cancer or fibrosis. METHODS: In this study, we identified miR-363 as a potent inducer of EMT by microarray analysis in human kidney tubular cells, and analyzed the function and mechanisms of miR-363. RESULTS: Overexpression of miR-363 induced mesenchymal phenotypes with loss of epithelial phenotypes in human kidney tubular cells. In addition, in vitro scratch assay demonstrated that miR-363 promotes cell migration of primary culture of human kidney tubular cells. We identified TWIST/canonical WNT pathway as the downstream effecter of miR-363, and inhibition of canonical WNT by small molecule, IWR-1, attenuated EMT induced by miR-363. CONCLUSION: miR-363 induces transdifferentiation of human kidney tubular cells via upregulation of TWIST/canonical WNT pathway.


Assuntos
Transdiferenciação Celular , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Túbulos Renais/metabolismo , MicroRNAs/metabolismo , Linhagem Celular , Movimento Celular , Transdiferenciação Celular/efeitos dos fármacos , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Humanos , Imidas/farmacologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , MicroRNAs/efeitos dos fármacos , MicroRNAs/genética , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Cultura Primária de Células , Quinolinas/farmacologia , Interferência de RNA , Ribonuclease III/genética , Ribonuclease III/metabolismo , Transfecção , Fator de Crescimento Transformador beta/farmacologia , Proteína 1 Relacionada a Twist/metabolismo , Via de Sinalização Wnt
15.
BMC Nephrol ; 16: 187, 2015 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-26554665

RESUMO

BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. CONCLUSION: In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not been recognized as a result of the renal involvement of PBC. PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver dysfunction.


Assuntos
Síndrome de Fanconi/diagnóstico , Fraturas Múltiplas/etiologia , Cirrose Hepática Biliar/complicações , Nefrite Intersticial/complicações , Osteomalacia/diagnóstico , Osteomalacia/etiologia , Diagnóstico Diferencial , Síndrome de Fanconi/complicações , Síndrome de Fanconi/terapia , Feminino , Fraturas Múltiplas/diagnóstico , Fraturas Múltiplas/terapia , Humanos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/terapia , Pessoa de Meia-Idade , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/terapia , Osteomalacia/terapia , Resultado do Tratamento
18.
Anal Chem ; 87(2): 1314-22, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25553788

RESUMO

A new method enabling sensitive real-time air monitoring of highly reactive chemical warfare agents, namely, mustard gas (HD) and Lewisite 1 (L1), by detecting ions of their in-line reaction products instead of intact agents, is proposed. The method is based on corona discharge-initiated atmospheric pressure chemical ionization coupled with ion trap tandem mass spectrometry (MS(n)) via counterflow ion introduction. Therefore, it allows for highly sensitive and specific real-time detection of a broad range of airborne compounds. In-line chemical reactions, ionization reactions, and ion fragmentations of these agents were investigated. Mustard gas is oxygenated in small quantity by reactive oxygen species generated in the corona discharge. With increasing air humidity, the MS(2) signal intensity of protonated molecules of mono-oxygenated HD decreases but exceeds that of dominantly existing intact HD. This result can be explained in view of proton affinity. Lewisite 1 is hydrolyzed and oxidized. As the humidity increases from zero, the signal of the final product, namely, didechlorinated, dihydroxylated, and mono-oxygenated L1, quickly increases and reaches a plateau, giving the highest MS(2) and MS(3) signals among those of L1 and its reaction products. The addition of minimal moisture gives the highest signal intensity, even under low humidity. The method was demonstrated to provide sufficient analytical performance to meet the requirements concerning hygienic management and counter-terrorism. It will be the first practical method, in view of sensitivity and specificity, for real-time air monitoring of HD and L1 without sample pretreatment.

19.
Sci Rep ; 4: 4578, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24694752

RESUMO

micro RNAs (miRNAs) are small non-coding RNAs that act as posttranscriptional repressors by binding to the 3'-UTR of target mRNAs. On the other hand, mesenchymal-epithelial transition (EMT) and kidney fibrosis is a pathological process of chronic kidney disease (CKD), and its relationship to miRNAs is becoming recognized as a potential target for CKD therapies. To find new miRNAs involved in EMT, we examined miRNA expression in experimental models of EMT and renal epithelialization using microarray, and found that miR-34c attenuates EMT induced by TGF-ß in a mouse tubular cell line. To confirm the effects of miR-34c in vivo, we administered the precursor of miR-34c to mice with unilateral ureteral obstruction, and miR-34c decreased kidney fibrosis area and the expression of connective tissue growth factor, α-SMA, collagen type 1, collagen type 3 and fibronectin. In conclusion, our study showed miR-34c attenuates EMT and kidney fibrosis of mice with ureteral obstruction.


Assuntos
Transição Epitelial-Mesenquimal , MicroRNAs/metabolismo , Obstrução Ureteral/patologia , Actinas/genética , Actinas/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Rim/metabolismo , Rim/patologia , Proteínas de Membrana/metabolismo , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Oligonucleotídeos Antissenso/metabolismo , Proteínas Serrate-Jagged , Fator de Crescimento Transformador beta/farmacologia , Obstrução Ureteral/genética
20.
Anal Chem ; 86(9): 4316-26, 2014 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-24678766

RESUMO

A highly sensitive and specific real-time field-deployable detection technology, based on counterflow air introduction atmospheric pressure chemical ionization, has been developed for a wide range of chemical warfare agents (CWAs) comprising gaseous (two blood agents, three choking agents), volatile (six nerve gases and one precursor agent, five blister agents), and nonvolatile (three lachrymators, three vomiting agents) agents in air. The approach can afford effective chemical ionization, in both positive and negative ion modes, for ion trap multiple-stage mass spectrometry (MS(n)). The volatile and nonvolatile CWAs tested provided characteristic ions, which were fragmented into MS(3) product ions in positive and negative ion modes. Portions of the fragment ions were assigned by laboratory hybrid mass spectrometry (MS) composed of linear ion trap and high-resolution mass spectrometers. Gaseous agents were detected by MS or MS(2) in negative ion mode. The limits of detection for a 1 s measurement were typically at or below the microgram per cubic meter level except for chloropicrin (submilligram per cubic meter). Matrix effects by gasoline vapor resulted in minimal false-positive signals for all the CWAs and some signal suppression in the case of mustard gas. The moisture level did influence the measurement of the CWAs.


Assuntos
Poluentes Atmosféricos/análise , Substâncias para a Guerra Química/análise , Espectrometria de Massas em Tandem/métodos , Pressão Atmosférica , Limite de Detecção
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